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Barghash RF, Gemmati D, Awad AM, Elbakry MMM, Tisato V, Awad K, Singh AV. Navigating the COVID-19 Therapeutic Landscape: Unveiling Novel Perspectives on FDA-Approved Medications, Vaccination Targets, and Emerging Novel Strategies. Molecules 2024; 29:5564. [PMID: 39683724 PMCID: PMC11643501 DOI: 10.3390/molecules29235564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/21/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Amidst the ongoing global challenge of the SARS-CoV-2 pandemic, the quest for effective antiviral medications remains paramount. This comprehensive review delves into the dynamic landscape of FDA-approved medications repurposed for COVID-19, categorized as antiviral and non-antiviral agents. Our focus extends beyond conventional narratives, encompassing vaccination targets, repurposing efficacy, clinical studies, innovative treatment modalities, and future outlooks. Unveiling the genomic intricacies of SARS-CoV-2 variants, including the WHO-designated Omicron variant, we explore diverse antiviral categories such as fusion inhibitors, protease inhibitors, transcription inhibitors, neuraminidase inhibitors, nucleoside reverse transcriptase, and non-antiviral interventions like importin α/β1-mediated nuclear import inhibitors, neutralizing antibodies, and convalescent plasma. Notably, Molnupiravir emerges as a pivotal player, now licensed in the UK. This review offers a fresh perspective on the historical evolution of COVID-19 therapeutics, from repurposing endeavors to the latest developments in oral anti-SARS-CoV-2 treatments, ushering in a new era of hope in the battle against the pandemic.
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Affiliation(s)
- Reham F. Barghash
- Institute of Chemical Industries Research, National Research Centre, Dokki, Cairo 12622, Egypt
- Faculty of Biotechnology, October University for Modern Sciences and Arts (MSA), Cairo 12451, Egypt
| | - Donato Gemmati
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Ahmed M. Awad
- Department of Chemistry, California State University Channel Islands, Camarillo, CA 93012, USA
| | - Mustafa M. M. Elbakry
- Faculty of Biotechnology, October University for Modern Sciences and Arts (MSA), Cairo 12451, Egypt
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo 11566, Egypt
| | - Veronica Tisato
- Centre Hemostasis & Thrombosis, University of Ferrara, 44121 Ferrara, Italy
| | - Kareem Awad
- Institute of Pharmaceutical and Drug Industries Research, National Research Center, Dokki, Cairo 12622, Egypt;
| | - Ajay Vikram Singh
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany
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McGinnis JH, Enriquez AB, Vandiver F, Bai X, Kim J, Kilgore J, Saha P, O'Hara R, Xie Y, Banaszynski LA, Williams N, McFadden DG. Endogenous EWSR1-FLI1 degron alleles enable control of fusion oncoprotein expression in tumor cell lines and xenografts. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.27.620498. [PMID: 39554175 PMCID: PMC11566046 DOI: 10.1101/2024.10.27.620498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Pediatric malignancies frequently harbor chromosomal translocations that induce expression of fusion oncoproteins. The EWSR1-FLI1 fusion oncoprotein acts as a neomorphic transcription factor and is the dominant genetic driver of Ewing's sarcoma. Interrogation of the mechanisms by which EWSR1-FLI1 drives tumorigenesis has been limited by a lack of model systems to precisely and selectively control its expression in patient-derived cell lines and xenografts. Here, we report the generation of a panel of patient-derived EWS cell lines in which inducible protein degrons were engineered into the endogenous EWSR1-FLI1 locus. These alleles enabled rapid and efficient depletion of EWSR1-FLI1. Complete suppression of EWSR1-FLI1 induced a reversible cell cycle arrest at the G 1 -S checkpoint, and we identified a core set of transcripts downstream of EWSR1-FLI1 across multiple cell lines and degron systems. Additionally, depletion of EWSR1-FLI1 potently suppressed tumor growth in xenograft models validating efforts to directly target EWSR1-FLI1 in Ewing's sarcoma.
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Samantaray M, Pattabiraman R, Murthy TPK, Ramaswamy A, Murahari M, Krishna S, Kumar SB. Structure-based virtual screening of natural compounds against wild and mutant (R1155K, A1156T and D1168A) NS3-4A protease of Hepatitis C virus. J Biomol Struct Dyn 2024; 42:8505-8522. [PMID: 37646701 DOI: 10.1080/07391102.2023.2246583] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 08/04/2023] [Indexed: 09/01/2023]
Abstract
NS3-4A, a serine protease, is a primary target for drug development against Hepatitis C Virus (HCV). However, the effectiveness of potent next-generation protease inhibitors is limited by the emergence of mutations and resulting drug resistance. To address this, in this study a structure-based drug design approach is employed to screen a large library of 7320 natural compounds against both wild-type and mutant variants of NS3-4A protease. Telaprevir, a widely used protease inhibitor, was recruited as the control drug. The top 10 compounds with favorable binding affinities underwent drug-likeness evaluation. Based on ADMET studies, complexes of NP_024762 and NP_006776 were selected for molecular dynamic simulations. Principal component analysis (PCA) was employed to explore the conformational space and protein dynamics of the protein-ligand complex using a Free Energy Landscape (FEL) approach. The cosine values obtained from FEL analysis ranged from 0 to 1, and eigenvectors with cosine values below 0.2 were chosen for further analysis. To forecast binding free energies and evaluate energy contributions per residue, the MM-PBSA method was employed. The results highlighted the crucial role of amino acids in the catalytic domain for the binding of the protease with phytochemicals. Stable associations between the top compounds and the target protease were confirmed by the formation of hydrogen bonds in the binding pocket involving residues: His1057, Gly1137, Ser1139, and Ala1157. These findings suggest the potential of these compounds for further validation through biological evaluation.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Mahesh Samantaray
- Department of Bioinformatics, Pondicherry University, Pondicherry, India
| | - Ramya Pattabiraman
- Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru, Karnataka, India
| | - T P Krishna Murthy
- Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru, Karnataka, India
| | - Amutha Ramaswamy
- Department of Bioinformatics, Pondicherry University, Pondicherry, India
| | - Manikanta Murahari
- Department of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, AP, India
| | - Swati Krishna
- Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru, Karnataka, India
| | - S Birendra Kumar
- Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru, Karnataka, India
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Niu ZX, Nie P, Herdewijn P, Wang YT. Synthetic approaches and application of clinically approved small-molecule drugs to treat hepatitis. Eur J Med Chem 2023; 262:115919. [PMID: 37922830 DOI: 10.1016/j.ejmech.2023.115919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 10/24/2023] [Accepted: 10/26/2023] [Indexed: 11/07/2023]
Abstract
Hepatitis, a global public health concern, presents a significant burden on healthcare systems worldwide. Particularly, hepatitis B and C are viral infections that can lead to severe liver damage, cirrhosis, and even hepatocellular carcinoma (HCC). The urgency to combat these diseases has driven researchers to explore existing small-molecule drugs as potential therapeutics. This comprehensive review provides a systematic overview of synthetic routes to key antiviral agents used to manage hepatitis. Furthermore, it elucidates the mechanisms of action of these drugs, shedding light on their interference with viral replication and liver disease progression. The review also discusses the clinical applications of these drugs, including their use in combination therapies and various patient populations. By evaluating the synthetic pathways and clinical utility of these drugs, this review not only consolidates current knowledge but also highlights potential future directions for research and drug development in the fight against hepatitis, ultimately contributing to improved patient outcomes and reduced global disease burden.
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Affiliation(s)
- Zhen-Xi Niu
- Department of Pharmacy, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, 450018, China
| | - Peng Nie
- Rega Institute for Medical Research, Medicinal Chemistry, KU Leuven, Herestraat 49-Box 1041, 3000, Leuven, Belgium.
| | - Piet Herdewijn
- Rega Institute for Medical Research, Medicinal Chemistry, KU Leuven, Herestraat 49-Box 1041, 3000, Leuven, Belgium.
| | - Ya-Tao Wang
- First People's Hospital of Shangqiu, Henan Province, Shangqiu, 476100, China; Department of Orthopedics, China-Japan Union Hospital, Jilin University, Changchun, 130033, China.
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Viral proteases as therapeutic targets. Mol Aspects Med 2022; 88:101159. [PMID: 36459838 PMCID: PMC9706241 DOI: 10.1016/j.mam.2022.101159] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022]
Abstract
Some medically important viruses-including retroviruses, flaviviruses, coronaviruses, and herpesviruses-code for a protease, which is indispensable for viral maturation and pathogenesis. Viral protease inhibitors have become an important class of antiviral drugs. Development of the first-in-class viral protease inhibitor saquinavir, which targets HIV protease, started a new era in the treatment of chronic viral diseases. Combining several drugs that target different steps of the viral life cycle enables use of lower doses of individual drugs (and thereby reduction of potential side effects, which frequently occur during long term therapy) and reduces drug-resistance development. Currently, several HIV and HCV protease inhibitors are routinely used in clinical practice. In addition, a drug including an inhibitor of SARS-CoV-2 main protease, nirmatrelvir (co-administered with a pharmacokinetic booster ritonavir as Paxlovid®), was recently authorized for emergency use. This review summarizes the basic features of the proteases of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and SARS-CoV-2 and discusses the properties of their inhibitors in clinical use, as well as development of compounds in the pipeline.
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Ashour NA, Abo Elmaaty A, Sarhan AA, Elkaeed EB, Moussa AM, Erfan IA, Al-Karmalawy AA. A Systematic Review of the Global Intervention for SARS-CoV-2 Combating: From Drugs Repurposing to Molnupiravir Approval. Drug Des Devel Ther 2022; 16:685-715. [PMID: 35321497 PMCID: PMC8935998 DOI: 10.2147/dddt.s354841] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 02/26/2022] [Indexed: 02/05/2023] Open
Abstract
The rising outbreak of SARS-CoV-2 continues to unfold all over the world. The development of novel effective antiviral drugs to fight against SARS-CoV-2 is a time cost. As a result, some specific FDA-approved drugs have already been repurposed and authorized for COVID-19 treatment. The repurposed drugs used were either antiviral or non-antiviral drugs. Accordingly, the present review thoroughly focuses on the repurposing efficacy of these drugs including clinical trials experienced, the combination therapies used, the novel methods followed for treatment, and their future perspective. Therefore, drug repurposing was regarded as an effective avenue for COVID-19 treatment. Recently, molnupiravir is a prodrug antiviral medication that was approved in the United Kingdom in November 2021 for the treatment of COVID-19. On the other hand, PF-07321332 is an oral antiviral drug developed by Pfizer. For the treatment of COVID-19, the PF-07321332/ritonavir combination medication is used in Phase III studies and was marketed as Paxlovid. Herein, we represented the almost history of combating COVID-19 from repurposing to the recently available oral anti-SARS-CoV-2 candidates, as a new hope to end the current pandemic.
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Affiliation(s)
- Nada A Ashour
- Department of Clinical Pharmacology, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
| | - Ayman Abo Elmaaty
- Department of Medicinal Chemistry, Faculty of Pharmacy, Port Said University, Port Said, 42526, Egypt
| | - Amany A Sarhan
- Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
| | - Eslam B Elkaeed
- Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Ad Diriyah, 13713, Riyadh, Saudi Arabia
| | - Ahmed M Moussa
- Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
| | - Ibrahim Ali Erfan
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
| | - Ahmed A Al-Karmalawy
- Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
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Sofia MJ. Curing Hepatitis C with Direct‐Acting Antiviral Therapy. METHODS AND PRINCIPLES IN MEDICINAL CHEMISTRY 2022:13-57. [DOI: 10.1002/9783527810697.ch2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Dowarah J, Marak BN, Yadav UCS, Singh VP. Potential drug development and therapeutic approaches for clinical intervention in COVID-19. Bioorg Chem 2021; 114:105016. [PMID: 34144277 PMCID: PMC8143914 DOI: 10.1016/j.bioorg.2021.105016] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/20/2021] [Indexed: 01/25/2023]
Abstract
While the vaccination is now available to many countries and will slowly dissipate to others, effective therapeutics for COVID-19 is still illusive. The SARS-CoV-2 pandemic has posed an unprecedented challenge to researchers, scientists, and clinicians and affected the wellbeing of millions of people worldwide. Since the beginning of the pandemic, a multitude of existing anti-viral, antibiotic, antimalarial, and anticancer drugs have been tested, and some have shown potency in the treatment and management of COVID-19, albeit others failed to leave any positive impact and a few also became controversial as they showed mixed clinical outcomes. In the present article, we have brought together some of the candidate therapeutic drugs being repurposed or used in the clinical trials and discussed their clinical efficacy and safety for COVID-19.
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Affiliation(s)
- Jayanta Dowarah
- Department of Chemistry, School of Physical Sciences, Mizoram University, Aizawl 796004, Mizoram, India
| | - Brilliant N Marak
- Department of Chemistry, School of Physical Sciences, Mizoram University, Aizawl 796004, Mizoram, India
| | | | - Ved Prakash Singh
- Department of Chemistry, School of Physical Sciences, Mizoram University, Aizawl 796004, Mizoram, India; Department of Industrial Chemistry, School of Physical Sciences, Mizoram University, Aizawl 796004, Mizoram, India.
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Pan S, Feng K, Huang P, Zeng Y, Ke L, Yang X, Liu J, Lin C. Efficacy and safety of danoprevir plus sofosbuvir in GT 1, 2, 3, or 6 chronic hepatitis C patients with or without cirrhosis in China. Medicine (Baltimore) 2021; 100:e26312. [PMID: 34128871 PMCID: PMC8213259 DOI: 10.1097/md.0000000000026312] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 05/08/2021] [Accepted: 05/24/2021] [Indexed: 01/04/2023] Open
Abstract
ABSTRACT All-oral direct-acting antiviral therapies are becoming the choice for hepatitis C (HCV) treatment. In this study, we aimed to evaluate the efficacy and safety of ritonavir-boosted danoprevir (DNVr) plus sofosbuvir±ribavirin on HCV genotype 1, 2, 3, or 6 in the real world in China.In this observational, prospective, multicenter cohort, we enrolled a total of 58 patients with HCV genotype 1, 2, 3, or 6 patients from July 2018 to December 2019. All patients were treated with DNVr plus sofosbuvir ± ribavirin for 12 weeks and then followed up for 12 weeks. The primary endpoint was the rate of sustained virologic response at week 12 after the end of treatment (SVR12). The secondary endpoint was virologic response rate at end-of-treatment and adverse event outcome.Of the 58 patients who were enrolled, 5.2% (n = 3) had genotype 1a; 43.1% (n = 25) had HCV genotype 1b; 17.2% (n = 10) had genotype 2a; 5.2% (n = 3) had genotype 3a; 8.6% (n = 5) had genotype 3b; and 20.7% (n = 12) had genotype 6a. The virologic response rate at end-of-treatment was 100% (58/58). The HCV-RNA results of 5 patients were absent at week 12 after treatment. Among the 53 patients, SVR12 rate achieved 100% (53/53) with DNVr plus sofosbuvir ± ribavirin treatment in patients with HCV genotype 1b, 2a, 3, and 6a. For compensated cirrhosis and noncirrhosis patients, SVR12 was 100% with DNVr plus sofosbuvir ± ribavirin treatment. No serious event was observed during the treatment and follow-up. Only 5 patients had mild adverse events.DNVr plus sofosbuvir ± ribavirin for 12 weeks provided 100% SVR12 in a broad patient population and were well tolerated, which may be a promising regimen for CHC treatment.
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Affiliation(s)
- Shufang Pan
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University
| | - Kai Feng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University
| | - Ping Huang
- Department of Infectious Diseases, The People's Hospital of Lianjiang, Guangdong Province
| | - Yingfu Zeng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University
| | - Liu Ke
- Liuzhou People's Hospital, Liuzhou, Guangxi
| | | | - Jing Liu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University
| | - Chaoshuang Lin
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University
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Singh A, Gupta V. SARS-CoV-2 therapeutics: how far do we stand from a remedy? Pharmacol Rep 2021; 73:750-768. [PMID: 33389724 PMCID: PMC7778692 DOI: 10.1007/s43440-020-00204-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/20/2020] [Accepted: 11/29/2020] [Indexed: 02/07/2023]
Abstract
The SARS-CoV-2 has affected millions worldwide and has posed an immediate need for effective pharmacological interventions. Ever since the outbreak was declared, the medical fraternity across the world is facing a unique situation of offering assistance and simultaneously generating reliable data with high-quality evidence to extend the scope of finding a treatment. With no proven vaccine or other interventions available hitherto, there is a frenzied urgency of sharing preliminary data from laboratories and trials to shape a global response against the virus. Several clinical trials with investigational and approved repurposed therapeutics have shown promising results. This review aims to compile the information of the reported molecules approved for emergency use and those under clinical trials and still others with good results in the studies conducted so far. Being an RNA virus, SARS-CoV-2 is prone to mutation; thus, the possibility of gaining resistance to available drugs is high. Consequently, a cocktail therapy based on drug interaction with different stages of its replicative cycle is desirable to reduce the chances of evolving drug resistance. Since this virus encodes several proteins, including 16 nonstructural and 4 structural proteins, this review also offers an insight into potential drug targets within SARS-CoV-2.
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Affiliation(s)
- Anurag Singh
- Department of Microbiology, Ram Lal Anand College, University of Delhi, Benito Juarez Road, New Delhi, 110021, India
| | - Vandana Gupta
- Department of Microbiology, Ram Lal Anand College, University of Delhi, Benito Juarez Road, New Delhi, 110021, India.
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Derruau S, Bouchet J, Nassif A, Baudet A, Yasukawa K, Lorimier S, Prêcheur I, Bloch-Zupan A, Pellat B, Chardin H, Jung S. COVID-19 and Dentistry in 72 Questions: An Overview of the Literature. J Clin Med 2021; 10:779. [PMID: 33669185 PMCID: PMC7919689 DOI: 10.3390/jcm10040779] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/09/2021] [Accepted: 02/11/2021] [Indexed: 02/06/2023] Open
Abstract
The outbreak of Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has significantly affected the dental care sector. Dental professionals are at high risk of being infected, and therefore transmitting SARS-CoV-2, due to the nature of their profession, with close proximity to the patient's oropharyngeal and nasal regions and the use of aerosol-generating procedures. The aim of this article is to provide an update on different issues regarding SARS-CoV-2 and COVID-19 that may be relevant for dentists. Members of the French National College of Oral Biology Lecturers ("Collège National des EnseignantS en Biologie Orale"; CNESBO-COVID19 Task Force) answered seventy-two questions related to various topics, including epidemiology, virology, immunology, diagnosis and testing, SARS-CoV-2 transmission and oral cavity, COVID-19 clinical presentation, current treatment options, vaccine strategies, as well as infection prevention and control in dental practice. The questions were selected based on their relevance for dental practitioners. Authors independently extracted and gathered scientific data related to COVID-19, SARS-CoV-2 and the specific topics using scientific databases. With this review, the dental practitioners will have a general overview of the COVID-19 pandemic and its impact on their practice.
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Affiliation(s)
- Stéphane Derruau
- UFR Odontologie, Université de Reims Champagne-Ardenne, 51100 Reims, France; (S.D.); (S.L.)
- Pôle de Médecine Bucco-dentaire, Centre Hospitalier Universitaire de Reims, 51092 Reims, France
- BioSpecT EA-7506, UFR de Pharmacie, Université de Reims Champagne-Ardenne, 51096 Reims, France
| | - Jérôme Bouchet
- UFR Odontologie-Montrouge, Université de Paris, 92120 Montrouge, France; (J.B.); (B.P.); (H.C.)
- Laboratory “Orofacial Pathologies, Imaging and Biotherapies” URP 2496, University of Paris, 92120 Montrouge, France
| | - Ali Nassif
- UFR Odontologie-Garancière, Université de Paris, 75006 Paris, France;
- AP-HP, Sites hospitaliers Pitié Salpêtrière et Rothschild, Service d’Orthopédie Dento-Faciale, Centre de Référence Maladies Rares Orales et Dentaires (O-Rares), 75013-75019 Paris, France
- INSERM, UMR_S 1138, Laboratoire de Physiopathologie Orale et Moléculaire, Centre de Recherche des Cordeliers, 75006 Paris, France
| | - Alexandre Baudet
- Faculté de Chirurgie Dentaire, Université de Lorraine, 54505 Vandœuvre-lès-Nancy, France; (A.B.); (K.Y.)
- Centre Hospitalier Régional Universitaire de Nancy, 54000 Nancy, France
| | - Kazutoyo Yasukawa
- Faculté de Chirurgie Dentaire, Université de Lorraine, 54505 Vandœuvre-lès-Nancy, France; (A.B.); (K.Y.)
- Centre Hospitalier Régional Universitaire de Nancy, 54000 Nancy, France
| | - Sandrine Lorimier
- UFR Odontologie, Université de Reims Champagne-Ardenne, 51100 Reims, France; (S.D.); (S.L.)
- Pôle de Médecine Bucco-dentaire, Centre Hospitalier Universitaire de Reims, 51092 Reims, France
- Université de Reims Champagne-Ardenne, MATIM EA, UFR Sciences, 51687 Reims, France
| | - Isabelle Prêcheur
- Faculté de Chirurgie Dentaire, Université Côte d’Azur, 06000 Nice, France;
- Pôle Odontologie, Centre Hospitalier Universitaire de Nice, 06000 Nice, France
- Laboratoire Microbiologie Orale, Immunothérapie et Santé (MICORALIS EA 7354), Faculté de Chirurgie Dentaire, 06300 Nice, France
| | - Agnès Bloch-Zupan
- Faculté de Chirurgie Dentaire, Université de Strasbourg, 67000 Strasbourg, France;
- Pôle de Médecine et de Chirurgie Bucco-Dentaires, Centre de Référence Maladies Rares Orales et Dentaires (O-Rares), Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, Université de Strasbourg, 67400 Illkirch-Graffenstaden, France
| | - Bernard Pellat
- UFR Odontologie-Montrouge, Université de Paris, 92120 Montrouge, France; (J.B.); (B.P.); (H.C.)
- Laboratory “Orofacial Pathologies, Imaging and Biotherapies” URP 2496, University of Paris, 92120 Montrouge, France
| | - Hélène Chardin
- UFR Odontologie-Montrouge, Université de Paris, 92120 Montrouge, France; (J.B.); (B.P.); (H.C.)
- AP-HP, Hôpital Henri Mondor, 94010 Créteil, France
- ESPCI, UMR CBI 8231, 75005 Paris, France
| | - Sophie Jung
- Faculté de Chirurgie Dentaire, Université de Strasbourg, 67000 Strasbourg, France;
- Pôle de Médecine et de Chirurgie Bucco-Dentaires, Centre de Référence Maladies Rares Orales et Dentaires (O-Rares), Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
- INSERM UMR_S 1109 «Molecular Immuno-Rheumatology», Institut Thématique Interdisciplinaire de Médecine de Précision de Strasbourg, Transplantex NG, Fédération hospitalo-universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France
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Xiao L, Wu X, Zhang F, Wang J, Xu X, Li L. Changes of inflammatory cytokines/chemokines during ravidasvir plus ritonavir-boosted danoprevir and ribavirin therapy for patients with genotype 1b hepatitis C infection. J Med Virol 2020; 92:3516-3524. [PMID: 32525562 DOI: 10.1002/jmv.26161] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/05/2020] [Accepted: 06/07/2020] [Indexed: 01/02/2023]
Abstract
This study investigated the safety and efficacy of ravidasvir (RDV) plus ritonavir-boosted danoprevir (DNVr) and ribavirin (RBV) regimens for treatment-naïve non-cirrhotic patients with hepatitis C virus (HCV) genotype 1b in mainland China. We also gained insight into HCV-host interactions during anti-HCV treatment. 16 patients with HCV and 10 healthy people enrolled the study. Three of 16 patients received 12-weeks' placebo treatment first and served as the placebo controls. All (n = 16) patients received 12-weeks' RDV plus DNVr and RBV treatment. The adverse effects (AEs), viral loads, alanine transaminase, and aspartate aminotransferase were recorded during study. We also performed multianalyte profiling of 48 cytokines/chemokines in 16 patients with HCV and 10 normal controls. Seventy-five percent patients treated with RDV plus DNVr and RBV experienced AEs. No death, treatment-related serious AEs or AEs leading to discontinuation were reported. The serum HCV-RNA levels remained extremely high in 3 placebo controls after treated with placebo. After RDV plus DNVr and RBV treatment, all patients achieved sustained virologic response (SVR) at posttreatment week 12, but 1 patient experienced viral relapse at SVR 24. The cytokine/chemokine expression pattern was markedly altered in patients with HCV as compared with healthy controls. The interferon-inducible protein-10 (IP-10) decreased after anti-HCV treatment, and dramatically increased in one patient with viral relapse. The regimen of RDV and DNVr plus RBV represents a highly safe and effective treatment option for HCV patients in mainland China. The IP-10 has the potential to be an indicator of innate immune viral recognition.
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Affiliation(s)
- Lanlan Xiao
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxin Wu
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fen Zhang
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jie Wang
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaowei Xu
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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13
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Chen H, Zhang Z, Wang L, Huang Z, Gong F, Li X, Chen Y, Wu JJ. First clinical study using HCV protease inhibitor danoprevir to treat COVID-19 patients. Medicine (Baltimore) 2020; 99:e23357. [PMID: 33235105 PMCID: PMC7710192 DOI: 10.1097/md.0000000000023357] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION As coronavirus disease 2019 (COVID-19) outbreak globally, repurposing approved drugs is emerging as important therapeutic options. Danoprevir boosted by ritonavir (Ganovo) is a potent hepatitis C virus (HCV) protease (NS3/4A) inhibitor, which was approved and marketed in China since 2018 to treat chronic hepatitis C patients. METHODS This is an open-label, single arm study evaluating the effects of danoprevir boosted by ritonavir on treatment naïve and experienced COVID-19 patients for the first time. Patients received danoprevir boosted by ritonavir (100 mg/100 mg, twice per day). The primary endpoint was the rate of composite adverse outcomes and efficacy was also evaluated. RESULTS The data showed that danoprevir boosted by ritonavir is safe and well tolerated in all patients. No patient had composite adverse outcomes during this study. After initiation of danoprevir/ritonavir treatment, the first negative reverse real-time PCR (RT-PCR) test occurred at a median of 2 days, ranging from 1 to 8 days, and the obvious absorption in CT scans occurred at a median 3 days, ranging from 2 to 4 days. After 4 to 12-day treatment of danoprevir boosted by ritonavir, all enrolled 11 patients were discharged from the hospital. CONCLUSION Our findings suggest that repurposing danoprevir for COVID-19 is a promising therapeutic option.
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Affiliation(s)
| | | | - Li Wang
- The First Department of Infectious Disease
| | | | - Fanghua Gong
- The Second Department of Infectious Disease, The Ninth Hospital of Nanchang, Nanchang 330002, Jiangxi Province
| | - Xiaodong Li
- Ascletis Bioscience Co., Ltd., Hangzhou 310051
| | - Yahong Chen
- Ascletis Bioscience Co., Ltd., Hangzhou 310051
| | - Jinzi J Wu
- Ascletis Bioscience Co., Ltd., Hangzhou 310051
- Ascletis Pharmaceuticals Co., Ltd., Shaoxing 310051, Zhejiang Province, China
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14
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Kouznetsov VV. COVID-19 treatment: Much research and testing, but far, few magic bullets against SARS-CoV-2 coronavirus. Eur J Med Chem 2020; 203:112647. [PMID: 32693298 PMCID: PMC7362854 DOI: 10.1016/j.ejmech.2020.112647] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 12/13/2022]
Abstract
The new virus of the of β-Coronaviruses genus, SARS-CoV-2, is the causative agent of coronavirus disease-2019 (COVID-19) and is winning a proverbial chess match against all players simultaneous, including physicians, clinicians, pathologists, doctors, scientists, economists, athletes and politicians. The COVID-19 outbreak has seriously threatened public health, killing the most vulnerable persons and causing general panic. To stop this disease, effective remedies (i.e., drugs, vaccines, personal protection elements, etc.) are urgently required. Unfortunately, no registered specific therapies (including antiviral therapies, immune-modulating agents and vaccines) are currently available to treat coronavirus infections, highlighting an urgent need for therapeutics targeting SARS-CoV-2. In this work, fourteen existing small molecule drugs or/and experimental drugs selected by experts and examined from the point of view of bioavailability via the Lipinski-Veber rules and assessment of their physicochemical descriptors. The aim of this study is to discover selected pattern similarities and peculiar characteristics that could be useful for antiviral drug optimization, drug combination or new antiviral agent design.
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15
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Kouznetsov VV. COVID-19 treatment: Much research and testing, but far, few magic bullets against SARS-CoV-2 coronavirus. Eur J Med Chem 2020. [PMID: 32693298 DOI: 10.1016/j.ejmech.2020.112647.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The new virus of the of β-Coronaviruses genus, SARS-CoV-2, is the causative agent of coronavirus disease-2019 (COVID-19) and is winning a proverbial chess match against all players simultaneous, including physicians, clinicians, pathologists, doctors, scientists, economists, athletes and politicians. The COVID-19 outbreak has seriously threatened public health, killing the most vulnerable persons and causing general panic. To stop this disease, effective remedies (i.e., drugs, vaccines, personal protection elements, etc.) are urgently required. Unfortunately, no registered specific therapies (including antiviral therapies, immune-modulating agents and vaccines) are currently available to treat coronavirus infections, highlighting an urgent need for therapeutics targeting SARS-CoV-2. In this work, fourteen existing small molecule drugs or/and experimental drugs selected by experts and examined from the point of view of bioavailability via the Lipinski-Veber rules and assessment of their physicochemical descriptors. The aim of this study is to discover selected pattern similarities and peculiar characteristics that could be useful for antiviral drug optimization, drug combination or new antiviral agent design.
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Affiliation(s)
- Vladimir V Kouznetsov
- Laboratorio de Química Orgánica y Biomolecular, CMN, Universidad Industrial de Santander, Parque Tecnológico Guatiguará, Piedecuesta, 681011, Colombia.
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16
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Miao M, Jing X, De Clercq E, Li G. Danoprevir for the Treatment of Hepatitis C Virus Infection: Design, Development, and Place in Therapy. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:2759-2774. [PMID: 32764876 PMCID: PMC7368560 DOI: 10.2147/dddt.s254754] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 06/12/2020] [Indexed: 12/12/2022]
Abstract
On June 8, 2018, an NS3/4A protease inhibitor called danoprevir was approved in China to treat the infections of HCV genotype (GT) 1b – the most common HCV genotype worldwide. Based on phase 2 and 3 clinical trials, the 12-week regimen of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a and ribavirin offered 97.1% (200/206) of sustained virologic response at post-treatment week 12 (SVR12) in treatment-naïve non-cirrhotic patients infected with HCV genotype 1b. Adverse events such as anemia, fatigue, fever, and headache were associated with the inclusion of peginterferon alpha-2a and ribavirin in the danoprevir-based regimen. Moreover, drug resistance to danoprevir could be traced to amino acid substitutions (Q80K/R, R155K, D168A/E/H/N/T/V) near the drug-binding pocket of HCV NS3 protease. Despite its approval, the clinical use of danoprevir is currently limited to its combination with peginterferon alpha-2a and ribavirin, thereby driving its development towards interferon-free, ribavirin-free regimens with improved tolerability and adherence. In the foreseeable future, pan-genotypic direct-acting antivirals with better clinical efficacy and less adverse events will be available to treat HCV infections worldwide.
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Affiliation(s)
- Miao Miao
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, People's Republic of China
| | - Xixi Jing
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, People's Republic of China
| | - Erik De Clercq
- Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven 3000, Belgium
| | - Guangdi Li
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, People's Republic of China
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17
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Mei H, Han J, White S, Graham DJ, Izawa K, Sato T, Fustero S, Meanwell NA, Soloshonok VA. Tailor-Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals. Chemistry 2020; 26:11349-11390. [PMID: 32359086 DOI: 10.1002/chem.202000617] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/23/2020] [Indexed: 12/11/2022]
Abstract
Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor-made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man-made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.
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Affiliation(s)
- Haibo Mei
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210037, P.R. China
| | - Jianlin Han
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210037, P.R. China
| | - Sarah White
- Oakwood Chemical, Inc., 730 Columbia Hwy. N, Estill, SC, 29918, USA
| | - Daniel J Graham
- Oakwood Chemical, Inc., 730 Columbia Hwy. N, Estill, SC, 29918, USA
| | - Kunisuke Izawa
- Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, 533-0024, Japan
| | - Tatsunori Sato
- Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, 533-0024, Japan
| | - Santos Fustero
- Departamento de Química Orgánica, Universidad de Valencia, 46100, Burjassot, Valencia, Spain
| | - Nicholas A Meanwell
- Department of Small Molecule Drug Discovery, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ, 08543-4000, USA
| | - Vadim A Soloshonok
- Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizábal 3, 20018, San Sebastián, Spain.,IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013, Bilbao, Spain
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18
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Impact of IFN-Free and IFN-Based Treatment on Blood Myeloid Dendritic Cell, Monocyte, Slan-DC, and Activated T Lymphocyte Dynamics during HCV Infection. J Immunol Res 2020; 2020:2781350. [PMID: 32258171 PMCID: PMC7102477 DOI: 10.1155/2020/2781350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 12/20/2019] [Accepted: 02/24/2020] [Indexed: 11/18/2022] Open
Abstract
Chronic hepatitis C virus infection leads to the activation of innate immunity, a key component in HCV fibrosis. In the past, the use of IFN-based treatment regimens did not permit an adequate evaluation of the impact of HCV clearance on immune cells, because of their antiviral and immunomodulatory properties. The recent development of direct-acting antiviral (DAA) therapy, which is associated with high rates of sustained virological response, enables a more accurate analysis of the immunological modifications following HCV eradication. We studied the dynamics of blood myeloid dendritic cells, monocytes, slan-DCs, and T lymphocytes during IFN-free and IFN-based regimens in hepatitis C virus infection.
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19
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Visualization of Positive and Negative Sense Viral RNA for Probing the Mechanism of Direct-Acting Antivirals against Hepatitis C Virus. Viruses 2019; 11:v11111039. [PMID: 31717338 PMCID: PMC6893808 DOI: 10.3390/v11111039] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/03/2019] [Accepted: 11/07/2019] [Indexed: 12/14/2022] Open
Abstract
RNA viruses are highly successful pathogens and are the causative agents for many important diseases. To fully understand the replication of these viruses it is necessary to address the roles of both positive-strand RNA ((+)RNA) and negative-strand RNA ((−)RNA), and their interplay with viral and host proteins. Here we used branched DNA (bDNA) fluorescence in situ hybridization (FISH) to stain both the abundant (+)RNA and the far less abundant (−)RNA in both hepatitis C virus (HCV)- and Zika virus-infected cells, and combined these analyses with visualization of viral proteins through confocal imaging. We were able to phenotypically examine HCV-infected cells in the presence of uninfected cells and revealed the effect of direct-acting antivirals on HCV (+)RNA, (−)RNA, and protein, within hours of commencing treatment. Herein, we demonstrate that bDNA FISH is a powerful tool for the study of RNA viruses that can provide insights into drug efficacy and mechanism of action.
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20
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Xu X, Feng B, Guan Y, Zheng S, Sheng J, Yang X, Ma Y, Huang Y, Kang Y, Wen X, Li J, Tan Y, He Q, Xie Q, Wang M, An P, Gong G, Liu H, Ning Q, Hua R, Ning B, Xie W, Zhang J, Huang W, Yang Y, Lin M, Zhao Y, Yu Y, Jia J, Yang D, Chen L, Ye Y, Nan Y, Gong Z, Zhang Q, Hu P, Wang F, Li Y, Li D, Jia Z, Hou J, Chen C, Wu JJ, Wei L. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China. J Clin Transl Hepatol 2019; 7:213-220. [PMID: 31608212 PMCID: PMC6783683 DOI: 10.14218/jcth.2019.00033] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/12/2019] [Accepted: 09/15/2019] [Indexed: 02/05/2023] Open
Abstract
Background and Aims: Ravidasvir (RDV) is a new generation pangenotypic hepatitis C virus (HCV) NS5A inhibitor, with high barrier to baseline resistance-associated species. This is the first phase 2/3 study conducted in Mainland China confirming the efficacy and safety of RDV + ritonavir-boosted danoprevir + ribavirin for 12 weeks in treatment-naïve noncirrhotic patients with genotype 1 infection in a large population. Methods: In this multicenter, randomized, double-blinded, placebo-controlled phase 2/3 trial (NCT03362814), we enrolled 424 treatment-naïve, noncirrhotic adult HCV genotype 1 patients. All patients were randomized at 3:1 ratio to receive a combination of RDV 200mg once daily plus ritonavir-boosted danoprevir 100mg/100mg twice daily and oral ribavirin 1000/1200mg/day (body weight <75/≥75 kg) (n = 318) or placebo (n = 106) for 12 weeks. The primary end-point was the rate of sustained virologic response 12 weeks after the end of treatment, and the safety was evaluated and compared between treatment and placebo groups. Results: The overall rate of sustained virological response at 12 weeks after treatment is 99% (306/309, 95%, CI: 97%-100%) under per protocol set analysis. All patients harboring baseline NS5A resistance-associated species in the treatment group (76/76, per protocol set) achieved sustained virological response at 12 weeks after treatment. No treatment-related serious adverse events were reported. Laboratory abnormalities showed mild or moderate severity (grade 1 and grade 2) in liver function tests. Conclusions: In treatment-naïve, noncirrhotic HCV Chinese patients infected with HCV genotype 1, all-oral regimen of RDV + ritonavir-boosted danoprevir + ribavirin for 12 weeks was highly efficacious, safe, and well tolerated.
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Affiliation(s)
- Xiaoyuan Xu
- Peking University First Hospital, Beijing, China
| | - Bo Feng
- Peking University People’s Hospital, Beijing, China
| | - Yujuan Guan
- Guangzhou Eighth People’s Hospital, Guangzhou, China
| | - Sujun Zheng
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Jifang Sheng
- The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, China
| | | | - Yuanji Ma
- West China Hospital, Sichuan University, Chengdu, China
| | - Yan Huang
- Xiangya Hospital, Central South University, Changsha, China
| | - Yi Kang
- Henan Provincial People’s Hospital, Zhengzhou, China
| | | | - Jun Li
- Jiangsu Province Hospital, Nanjing, China
| | - Youwen Tan
- Zhenjiang No.3 People’s Hospital, Zhenjiang, China
| | - Qing He
- The Third People’s Hospital of Shenzhen, Shenzhen, China
| | - Qing Xie
- Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Maorong Wang
- People’s Liberation Army Bayi Hospital, Nanjing, China
| | - Ping An
- Shenyang Sixth People’s Hospital, Shenyang, China
| | - Guozhong Gong
- The 2nd Xiangya Hospital of Central South University, Changsha, China
| | - Huimin Liu
- Xixi Hospital of Hangzhou, Hangzhou, China
| | - Qin Ning
- Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China
| | - Rui Hua
- The First Hospital of Jilin University, Changchun, China
| | - Bo Ning
- Baoji Center Hospital, Baoji, China
| | - Wen Xie
- Beijing Ditan Hospital, Beijing, China
| | - Jiming Zhang
- Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Wenxiang Huang
- Chongqing Medical University No.1 Affiliated Hospital, Chongqing, China
| | | | - Minghua Lin
- Fujian Fuzhou Municipal Infectious Disease Hospital, Fuzhou, China
| | - Yingren Zhao
- No.1 Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yanhong Yu
- The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | | | - Liang Chen
- Shanghai Public Health Clinical Center, Shanghai, China
| | - Yinong Ye
- Foshan No.1 People’s Hospital, Foshan, China
| | - Yuemin Nan
- The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | | | - Quan Zhang
- The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Peng Hu
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | | | - Yongguo Li
- The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dongliang Li
- Fuzhou General Hospital of Nanjing Military Command, Fuzhou, China
| | - Zhansheng Jia
- Tang Du Hospital, Fourth military Medical University, Xi’an, China
| | - Jinlin Hou
- Nanfang Hospital, Nanfang Medical University, Guangzhou, China
| | - Chengwei Chen
- The 85 branch of the Chinese People’s Liberation Army Hospital, Shanghai, China
| | - Jinzi J. Wu
- Ascletis BioScience Co., Ltd. Hangzhou, China
| | - Lai Wei
- Tsinghua Changgeng Hospital, Beijing, China
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Özen A, Prachanronarong K, Matthew AN, Soumana DI, Schiffer CA. Resistance outside the substrate envelope: hepatitis C NS3/4A protease inhibitors. Crit Rev Biochem Mol Biol 2019; 54:11-26. [PMID: 30821513 DOI: 10.1080/10409238.2019.1568962] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Direct acting antivirals have dramatically increased the efficacy and tolerability of hepatitis C treatment, but drug resistance has emerged with some of these inhibitors, including nonstructural protein 3/4 A protease inhibitors (PIs). Although many co-crystal structures of PIs with the NS3/4A protease have been reported, a systematic review of these crystal structures in the context of the rapidly emerging drug resistance especially for early PIs has not been performed. To provide a framework for designing better inhibitors with higher barriers to resistance, we performed a quantitative structural analysis using co-crystal structures and models of HCV NS3/4A protease in complex with natural substrates and inhibitors. By comparing substrate structural motifs and active site interactions with inhibitor recognition, we observed that the selection of drug resistance mutations correlates with how inhibitors deviate from viral substrates in molecular recognition. Based on this observation, we conclude that guiding the design process with native substrate recognition features is likely to lead to more robust small molecule inhibitors with decreased susceptibility to resistance.
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Affiliation(s)
- Ayşegül Özen
- a Department of Biochemistry and Molecular Pharmacology , University of Massachusetts Medical School , Worcester , MA , USA
| | - Kristina Prachanronarong
- a Department of Biochemistry and Molecular Pharmacology , University of Massachusetts Medical School , Worcester , MA , USA
| | - Ashley N Matthew
- a Department of Biochemistry and Molecular Pharmacology , University of Massachusetts Medical School , Worcester , MA , USA
| | - Djade I Soumana
- a Department of Biochemistry and Molecular Pharmacology , University of Massachusetts Medical School , Worcester , MA , USA
| | - Celia A Schiffer
- a Department of Biochemistry and Molecular Pharmacology , University of Massachusetts Medical School , Worcester , MA , USA
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22
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Schumann NC, Bruning J, Marshall AC, Abell AD. The role of N-terminal heterocycles in hydrogen bonding to α-chymotrypsin. Bioorg Med Chem Lett 2019; 29:396-399. [PMID: 30579793 DOI: 10.1016/j.bmcl.2018.12.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 12/11/2018] [Accepted: 12/14/2018] [Indexed: 01/14/2023]
Abstract
A series of dipeptide aldehydes containing different N-terminal heterocycles was prepared and assayed in vitro against α-chymotrypsin to ascertain the importance of the heterocycle in maintaining a β-strand geometry while also providing a hydrogen bond donor equivalent to the backbone amide nitrogen of the surrogate amino acid. The dipeptide containing a pyrrole constraint (10) was the most potent inhibitor, with >30-fold improved activity over dipeptides which lacked a nitrogen hydrogen bond donor (namely thiophene 11, furan 12 and pyridine 13). Molecular docking studies of 10 bound to α-chymotrypsin demonstrates a hydrogen bond between the pyrrole nitrogen donor and the backbone carbonyl of Gly216 located in the S3 pocket which is proposed to be critical for overall binding.
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Affiliation(s)
- Nicholas C Schumann
- School of Chemistry & Physics, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia
| | - John Bruning
- School of Biological Sciences, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia
| | - Andrew C Marshall
- School of Biological Sciences, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia
| | - Andrew D Abell
- School of Chemistry & Physics, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia; ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP) and Institute of Photonics and Advanced Sensing (IPAS), The University of Adelaide, Adelaide, South Australia 5005, Australia.
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23
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Liverton NJ. Evolution of HCV NS3/4a Protease Inhibitors. TOPICS IN MEDICINAL CHEMISTRY 2019. [DOI: 10.1007/7355_2018_39] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Zhai PB, Qing J, Li B, Zhang LQ, Ma L, Chen L. GP205, a new hepatitis C virus NS3/4A protease inhibitor, displays higher metabolic stability in vitro and drug exposure in vivo. Acta Pharmacol Sin 2018; 39:1746-1752. [PMID: 29930277 DOI: 10.1038/s41401-018-0046-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 05/12/2018] [Indexed: 12/14/2022]
Abstract
NS3/4A serine protease is a prime target for direct-acting antiviral therapies against hepatitis C virus (HCV) infection. Several NS3/4A inhibitors have been widely used in clinic, while new inhibitors with better characteristics are still urgently needed. GP205 is a new macrocyclic inhibitor of NS3/4A with low nanomolar activities against HCV replicons of genotypes 1b, 2a, 4a, and 5a, with EC50 values ranging from 1.5 to 12.8 nmol/L. In resistance selection study in vitro, we found resistance-associated substitutions on D168: The activity of GP205 was significantly attenuated against 1b replicon with D168V or D168A mutation, similar as simeprevir. No cross resistance of GP205 with NS5B or NS5A inhibitor was observed. Combination of GP205 with sofosbuvir or daclatasvir displayed additive or synergistic efficacy. The pharmacokinetic profile of GP205 was characterized in rats and dogs after oral administration, which revealed good drug exposure both in plasma and in liver and long plasma half-life. The in vitro stability test showed ideal microsomal and hepatic cells stability of GP205. The preclinical profiles of GP205 support further research on this NS3/4A inhibitor to expand the existing HCV infection therapies.
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25
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Tague EP, Dotson HL, Tunney SN, Sloas DC, Ngo JT. Chemogenetic control of gene expression and cell signaling with antiviral drugs. Nat Methods 2018; 15:519-522. [PMID: 29967495 DOI: 10.1038/s41592-018-0042-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 04/24/2018] [Indexed: 02/04/2023]
Abstract
We developed a method in which the NS3 cis-protease from hepatitis C virus can be used as a ligand-inducible connection to control the function and localization of engineered proteins in mammalian cells. To demonstrate the versatility of this approach, we designed drug-sensitive transcription factors and transmembrane signaling proteins, the activities of which can be tightly and reversibly controlled through the use of clinically tested antiviral protease inhibitors.
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Affiliation(s)
- Elliot P Tague
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA
| | - Hannah L Dotson
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA
| | - Shannon N Tunney
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA
| | - D Christopher Sloas
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA
| | - John T Ngo
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA.
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26
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Mandour M, Vliegen I, Paeshuyse J, Neyts J. Rational design of antiviral drug combinations based on equipotency using HCV subgenomic replicon as an in vitro model. Antiviral Res 2017; 149:150-153. [PMID: 29154807 DOI: 10.1016/j.antiviral.2017.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 10/24/2017] [Accepted: 11/07/2017] [Indexed: 10/18/2022]
Abstract
Combination therapy of directly acting antivirals (DAA's) for the treatment of chronic HCV infections has proven to be a highly effective strategy to cure chronic infections with this virus. Here we studied, using HCV as an example, how to best design in vitro studies that explore the combined antiviral efficiency of combinations of three or more DAA's. To that end we used a HCV NS3 protease inhibitor, a NS5A targeting compound and two non-nucleoside NS5B polymerase inhibitors (each one targeting a different drug binding site). We demonstrate, employing HCV subgenomic replicon containing Huh 9-13 hepatoma cells, that quadruple therapy with these 4 different DAA's each at 1x their EC75, results in a highly efficient inhibition of viral replication. This is further reflected in the rapid clearance of the HCV replicon from the host cell. By contrast, neither equipotent combinations that consist of either molecules alone at 4x EC75 nor triple combinations at 1.33x the EC75 resulted in clearance. In contrast to the quadruple combo, drug-resistant variants emerged under mono-treatment and in most triple combo's. These data thus demonstrate that quadruple combinations at total suboptimal concentrations [i.e. concentrations at which neither mono- nor triple therapy is sufficiently potent] result rapidly in a pronounced antiviral efficacy. Altogether, this work provides an example as to how to design studies to explore the antiviral efficacy of combinations of more than two compounds.
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Affiliation(s)
- Mohamed Mandour
- Rega Institute for Medical Research, University of Leuven (KU Leuven), B-3000 Leuven, Belgium; Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Inge Vliegen
- Rega Institute for Medical Research, University of Leuven (KU Leuven), B-3000 Leuven, Belgium
| | - Jan Paeshuyse
- KU Leuven, Department of Biosystems, Division Animal and Human Health Engineering, Host Pathogen Interactions, B-3001 Leuven, Belgium.
| | - Johan Neyts
- Rega Institute for Medical Research, University of Leuven (KU Leuven), B-3000 Leuven, Belgium
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27
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Guo X, Wang S, Qiu ZG, Dou YL, Liu WL, Yang D, Shen ZQ, Chen ZL, Wang JF, Zhang B, Wang XW, Guo XF, Zhang XL, Jin M, Li JW. Efficient replication of blood-borne hepatitis C virus in human fetal liver stem cells. Hepatology 2017; 66:1045-1057. [PMID: 28407288 DOI: 10.1002/hep.29211] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 04/05/2017] [Indexed: 02/06/2023]
Abstract
UNLABELLED The development of pathogenic mechanisms, specific antiviral treatments and preventive vaccines for hepatitis C virus (HCV) infection has been limited due to lack of cell culture models that can naturally imitate the entire HCV life cycle. Here, we established an HCV cell culture model based on human fetal liver stem cells (hFLSCs) that supports the entire blood-borne hepatitis C virus (bbHCV) life cycle. More than 90% of cells remained infected by various genotypes. bbHCV was efficiently propagated, and progeny virus were infectious to hFLSCs. The virus could be passed efficiently between cells. The viral infectivity was partially blocked by specific antibodies or small interfering RNA against HCV entry factors, whereas HCV replication was inhibited by antiviral drugs. We observed viral particles of approximately 55 nm in diameter in both cell culture media and infected cells after bbHCV infection. CONCLUSION Our data show that the entire bbHCV life cycle could be naturally imitated in hFLSCs. This model is expected to provide a powerful tool for exploring the process and the mechanism of bbHCV infection at the cellular level and for evaluating the treatment and preventive strategies of bbHCV infection. (Hepatology 2017;66:1045-1057).
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Affiliation(s)
- Xuan Guo
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Shu Wang
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Zhi-Gang Qiu
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Ya-Ling Dou
- Peking Union Medical College Hospital, Chinese Medical Academy, Beijing, China
| | - Wei-Li Liu
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Dong Yang
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Zhi-Qiang Shen
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Zhao-Li Chen
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Jing-Feng Wang
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Bin Zhang
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Xin-Wei Wang
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Xiang-Fei Guo
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Xue-Lian Zhang
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Min Jin
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
| | - Jun-Wen Li
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin, China
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28
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Meeprasert A, Hannongbua S, Kungwan N, Rungrotmongkol T. Effect of D168V mutation in NS3/4A HCV protease on susceptibilities of faldaprevir and danoprevir. MOLECULAR BIOSYSTEMS 2017; 12:3666-3673. [PMID: 27731877 DOI: 10.1039/c6mb00610h] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Hepatitis C virus (HCV) is a serious cause of liver inflammation, cirrhosis and the development of hepatocellular carcinoma. Its NS3/4A serine protease functions to cleave a specific peptide bond, which is an important step in HCV replication. Thus the NS3/4A protease has become one of the main drug-targets in the design and development of anti-HCV agents. Unfortunately, high mutation rates in HCV have been reported due to the lack of RNA proofreading activity resulting in drug resistance. Herein, all-atom molecular dynamics simulations were employed to understand and illustrate the effects of the NS3/4A D168V mutation on faldaprevir (FDV) and danoprevir (DNV) binding efficiency. The D168V mutation was shown to interrupt the hydrogen bonding network of Q80R155D168R123 embedded in the extended S2 and partial S4 subsites of the NS3 protein and as a result the R123 side chain was displaced and moved out from the binding pocket. By means of MM/PBSA and MM/GBSA binding free energy calculations, the FDV and DNV binding affinities were shown to be significantly reduced by ∼10-15 kcal mol-1 and ∼4-9 kcal mol-1 relative to the wild-type complexes, respectively, which somewhat agrees with the experimental resistance folds.
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Affiliation(s)
- Arthitaya Meeprasert
- Structural and Computational Biology Research Group, Department of Biochemistry, Faculty of Science Chulalongkorn University, 254, Phayathai Road, Pathumwan, Bangkok 10330, Thailand
| | - Supot Hannongbua
- Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Pathumwan, Bangkok 10330, Thailand
| | - Nawee Kungwan
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Thanyada Rungrotmongkol
- Structural and Computational Biology Research Group, Department of Biochemistry, Faculty of Science Chulalongkorn University, 254, Phayathai Road, Pathumwan, Bangkok 10330, Thailand and PhD Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
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29
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Hamada Y, Kiso Y. New directions for protease inhibitors directed drug discovery. Biopolymers 2016; 106:563-79. [PMID: 26584340 PMCID: PMC7161749 DOI: 10.1002/bip.22780] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 10/25/2015] [Accepted: 11/02/2015] [Indexed: 12/29/2022]
Abstract
Proteases play crucial roles in various biological processes, and their activities are essential for all living organisms-from viruses to humans. Since their functions are closely associated with many pathogenic mechanisms, their inhibitors or activators are important molecular targets for developing treatments for various diseases. Here, we describe drugs/drug candidates that target proteases, such as malarial plasmepsins, β-secretase, virus proteases, and dipeptidyl peptidase-4. Previously, we reported inhibitors of aspartic proteases, such as renin, human immunodeficiency virus type 1 protease, human T-lymphotropic virus type I protease, plasmepsins, and β-secretase, as drug candidates for hypertension, adult T-cell leukaemia, human T-lymphotropic virus type I-associated myelopathy, malaria, and Alzheimer's disease. Our inhibitors are also described in this review article as examples of drugs that target proteases. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 563-579, 2016.
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Affiliation(s)
- Yoshio Hamada
- Medicinal Chemistry LaboratoryKobe Pharmaceutical University, MotoyamakitaHigashinada‐kuKobe658‐8558Japan
| | - Yoshiaki Kiso
- Laboratory of Peptide Science, Nagahama Institute of Bio‐Science and TechnologyTamura‐choNagahama526‐0829Japan
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30
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Sun L, Gao P, Zhan P, Liu X. Pyrazolo[1,5-a]pyrimidine-based macrocycles as novel HIV-1 inhibitors: a patent evaluation of WO2015123182. Expert Opin Ther Pat 2016; 26:979-86. [PMID: 27398994 DOI: 10.1080/13543776.2016.1210127] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The emergence of drug resistance in Combination Antiretroviral Therapy (cART) confirms a continuing need to investigate novel HIV-1 inhibitors with unexplored mechanisms of action. Recently, a series of pyrazolopyrimidine-based macrocyclic compounds were reported as inhibitors of HIV-1 replication disclosed in the patent WO2015123182. Most of the disclosed compounds possessed in vitro antiviral potency in single-digit nanomolar range, which were determined by MT-2 cell assay. Then, the structural diversity, pharmacophore similarity of HIV-1 IN-LEDGF/p75 inhibitors, and implications for drug design were analyzed. In the end of this article, a glimpse of some macrocycles as potent antiviral agents (drug candidates) was provided. Some strategies and technologies enabling macrocycle design were also described. We expect that further development of these macrocyclic compounds will offer new anti-HIV-1 drug candidates.
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Affiliation(s)
- Lin Sun
- a Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University , Jinan , P. R. China
| | - Ping Gao
- a Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University , Jinan , P. R. China
| | - Peng Zhan
- a Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University , Jinan , P. R. China
| | - Xinyong Liu
- a Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University , Jinan , P. R. China
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31
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Spindelboeck W, Horvath A, Tawdrous M, Schmerböck B, Zettel G, Posch A, Streit A, Jurse P, Lemesch S, Horn M, Wuensch G, Stiegler P, Stauber RE, Leber B, Stadlbauer V. Triple Therapy with First Generation Protease Inhibitors for Hepatitis C Markedly Impairs Function of Neutrophil Granulocytes. PLoS One 2016; 11:e0150299. [PMID: 26938078 PMCID: PMC4777445 DOI: 10.1371/journal.pone.0150299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 02/11/2016] [Indexed: 01/01/2023] Open
Abstract
First-generation HCV protease inhibitors represent a milestone in antiviral therapy for chronic hepatitis C infection (CHC), but substantially increased rates of viral clearance are offset by increased rates of infection and infection-associated deaths, especially of patients with advanced liver disease. We aimed to assess whether first generation protease inhibitors interfere with neutrophil function. We included 108 consecutive, retrospective CHC patients and 44 consecutive, prospective CHC patients who were treated with peginterferon and ribavirin with or without protease inhibitors according to the guidelines in the period of November 2012 to June 2015. 33 healthy volunteers served as controls. Infection data were evaluated in all patients. Neutrophil phagocytosis, oxidative burst, elastase and diamine oxidase levels during 12 weeks of triple (n = 23) or dual therapy (n = 21) were studied in the prospective part. In the retro- and prospective cohorts patients experiencing clinically relevant infections were significantly more frequent during protease inhibitor therapy (31% and 26%) than during therapy with peginterferon and ribavirin (13% and 0%). Neutrophil phagocytosis decreased to 40% of baseline with addition of protease inhibitors to P/R but recovered 6 months after end of treatment. Protease inhibitors also seemed to reduce serum elastase levels but did not impact on gut permeability. Impaired neutrophil function during triple therapy with first generation HCV protease inhibitors may explain the high infection rate associated to these treatments and be of relevance for treatment success and patient survival.
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Affiliation(s)
- Walter Spindelboeck
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Angela Horvath
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Monika Tawdrous
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Bianca Schmerböck
- Department of Surgery, Division of Transplantation Surgery, Medical University of Graz, Graz, Austria
| | - Gabriele Zettel
- Department of Surgery, Division of Transplantation Surgery, Medical University of Graz, Graz, Austria
| | - Andreas Posch
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Andrea Streit
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Petra Jurse
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Sandra Lemesch
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Martin Horn
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Gerit Wuensch
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Philipp Stiegler
- Department of Surgery, Division of Transplantation Surgery, Medical University of Graz, Graz, Austria
| | - Rudolf E. Stauber
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Bettina Leber
- Department of Surgery, Division of Transplantation Surgery, Medical University of Graz, Graz, Austria
- * E-mail:
| | - Vanessa Stadlbauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
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32
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Synthetic Strategy and Anti-Tumor Activities of Macrocyclic Scaffolds Based on 4-Hydroxyproline. Molecules 2016; 21:molecules21020212. [PMID: 26891283 PMCID: PMC6274554 DOI: 10.3390/molecules21020212] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Revised: 02/03/2016] [Accepted: 02/04/2016] [Indexed: 01/13/2023] Open
Abstract
A series of novel 13- to 15-member hydroxyproline-based macrocycles, which contain alkyl-alkyl ether and alkyl-aryl ether moieties, have been synthesized by the strategy of macrocyclization utilising azide-alkyne cycloaddition, Mitsunobu protocol and amide formation. Their anti-tumor activities towards A549, MDA-MB-231 and Hep G2 cells were screened in vitro by an MTT assay. The results indicated that 13-member macrocycle 33 containing alkene chain showed the best results, exhibiting the highest inhibitory effects towards lung cancer cell line A549, which was higher than that of the reference cisplatin (IC50 value = 2.55 µmol/L).
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33
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Nagpal N, Goyal S, Wahi D, Jain R, Jamal S, Singh A, Rana P, Grover A. Molecular principles behind Boceprevir resistance due to mutations in hepatitis C NS3/4A protease. Gene 2015; 570:115-121. [PMID: 26055089 DOI: 10.1016/j.gene.2015.06.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 05/28/2015] [Accepted: 06/03/2015] [Indexed: 02/05/2023]
Abstract
The hepatitis C virus (HCV) infection is a primary cause of chronic hepatitis which eventually progresses to cirrhosis and in some instances might advance to hepatocellular carcinoma. According to the WHO report, HCV infects 130-150 million people globally and every year 350,000 to 500,000 people die from hepatitis C virus infection. Great achievement has been made in viral treatment evolution, after the development of HCV NS3/4A protease inhibitor (Boceprevir). However, efficacy of Boceprevir is compromised by the emergence of drug resistant variants. The molecular principle behind drug resistance of the protease mutants such as (V36M, T54S and R155K) is still poorly understood. Therefore in this study, we employed a series of computational strategies to analyze the binding of antiviral drug, Boceprevir to HCV NS3/4A protease mutants. Our results clearly demonstrate that the point mutations (V36M, T54S and R155K) in protease are associated with lowering of its binding affinity with Boceprevir. Exhaustive analysis of the simulated Boceprevir-bound wild and mutant complexes revealed variations in hydrophobic interactions, hydrogen bond occupancy and salt bridge interactions. Also, substrate envelope analysis scrutinized that the studied mutations reside outside the substrate envelope which may affect the Boceprevir affinity towards HCV protease but not the protease enzymatic activity. Furthermore, structural analyses of the binding site volume and flexibility show impairment in flexibility and stability of the binding site residues in mutant structures. In order to combat Boceprevir resistance, renovation of binding interactions between the drug and protease may be valuable. The structural insight from this study reveals the mechanism of the Boceprevir resistance and the results can be valuable for the design of new PIs with improved efficiency.
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Affiliation(s)
- Neha Nagpal
- Department of Biotechnology, Delhi Technological University, Delhi 110042, India
| | - Sukriti Goyal
- Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan 304022, India
| | - Divya Wahi
- School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Ritu Jain
- School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Salma Jamal
- Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan 304022, India
| | - Aditi Singh
- School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Preeti Rana
- School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Abhinav Grover
- School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
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34
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Mosure KW, Knipe JO, Browning M, Arora V, Shu YZ, Phillip T, Mcphee F, Scola P, Balakrishnan A, Soars MG, Santone K, Sinz M. Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor. J Pharm Sci 2015; 104:2813-23. [DOI: 10.1002/jps.24356] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 12/23/2014] [Accepted: 12/23/2014] [Indexed: 12/11/2022]
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35
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Yang N, Sun Q, Xu Z, Wang X, Zhao X, Cao Y, Chen L, Fan G. LC-ESI-MS/MS analysis and pharmacokinetics of GP205, an innovative potent macrocyclic inhibitor of hepatitis C virus NS3/4A protease in rats. Molecules 2015; 20:4319-36. [PMID: 25756650 PMCID: PMC6272426 DOI: 10.3390/molecules20034319] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Revised: 02/12/2015] [Accepted: 02/25/2015] [Indexed: 12/12/2022] Open
Abstract
A high-throughput, sensitive and specific LC-ESI-MS/MS method was established for the quantitative determination of GP205, a potent inhibitor of hepatitis C virus NS3/4A protease, in rat. The analyte was isolated from 25 μL plasma sample by 96-well LLE. Good linearity was achieved within the concentration range of 2–5000 ng/mL (r2 > 0.996). The intra- and inter-day precision was less than 10%. The accuracy ranged from 0.8% to 5.5% for GP205 in quality control samples at three levels. GP205 was stable during the analysis and the storage period. The method was successfully applied to pharmacokinetic studies of GP205 in Sprague-Dawley rats. The pharmacokinetic profiles of GP205 at three dose levels with oral administration and one dose level with intravenous administration were successfully studied for the first time in SD rats, respectively. After single oral administration of GP205 at the doses of 2.5, 5, 10 mg/kg, respectively, Cmax and AUC0-τ were proportional to the doses given. The absolute bioavailability was estimated as 34% based on the AUCs of oral administration at the dose of 5 mg/kg and intravenous administration at the dose of 1 mg/kg. The data presented in this study provides useful information for further study for GP205.
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Affiliation(s)
- Nan Yang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China.
| | - Qiushi Sun
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China.
| | - Zihua Xu
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China.
| | - Xiuyun Wang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China.
- Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China.
| | - Xin Zhao
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China.
| | - Yuqing Cao
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China.
| | - Li Chen
- Ginkgo Pharma Co. Ltd., Suzhou 205125, China.
| | - Guorong Fan
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China.
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36
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Preciado MV, Valva P, Escobar-Gutierrez A, Rahal P, Ruiz-Tovar K, Yamasaki L, Vazquez-Chacon C, Martinez-Guarneros A, Carpio-Pedroza JC, Fonseca-Coronado S, Cruz-Rivera M. Hepatitis C virus molecular evolution: Transmission, disease progression and antiviral therapy. World J Gastroenterol 2014; 20:15992-16013. [PMID: 25473152 PMCID: PMC4239486 DOI: 10.3748/wjg.v20.i43.15992] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 06/22/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection represents an important public health problem worldwide. Reduction of HCV morbidity and mortality is a current challenge owned to several viral and host factors. Virus molecular evolution plays an important role in HCV transmission, disease progression and therapy outcome. The high degree of genetic heterogeneity characteristic of HCV is a key element for the rapid adaptation of the intrahost viral population to different selection pressures (e.g., host immune responses and antiviral therapy). HCV molecular evolution is shaped by different mechanisms including a high mutation rate, genetic bottlenecks, genetic drift, recombination, temporal variations and compartmentalization. These evolutionary processes constantly rearrange the composition of the HCV intrahost population in a staging manner. Remarkable advances in the understanding of the molecular mechanism controlling HCV replication have facilitated the development of a plethora of direct-acting antiviral agents against HCV. As a result, superior sustained viral responses have been attained. The rapidly evolving field of anti-HCV therapy is expected to broad its landscape even further with newer, more potent antivirals, bringing us one step closer to the interferon-free era.
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37
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Soumana DI, Ali A, Schiffer CA. Structural analysis of asunaprevir resistance in HCV NS3/4A protease. ACS Chem Biol 2014; 9:2485-90. [PMID: 25243902 PMCID: PMC4245159 DOI: 10.1021/cb5006118] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
![]()
Asunaprevir (ASV), an isoquinoline-based
competitive inhibitor
targeting the hepatitis C virus (HCV) NS3/4A protease, is very potent in vivo. However, the potency is significantly compromised
by the drug resistance mutations R155K and D168A. In this study three
crystal structures of ASV and an analogue were determined to analyze
the structural basis of drug resistance susceptibility. These structures
revealed that ASV makes extensive contacts with Arg155 outside the
substrate envelope. Arg155 in turn is stabilized by Asp168, and thus
when either residue is mutated, the enzyme’s interaction with
ASV’s P2* isoquinoline is disrupted. Adding a P1–P3 macrocycle to ASV enhances the inhibitor’s
resistance barrier, likely due to poising the inhibitor to its bound
conformation. Macrocyclic inhibitors with P2* extension
moieties avoiding interaction with the protease S2 residues
including Arg155 must be chosen for future design of more robust protease
inhibitors.
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Affiliation(s)
- Djadé I. Soumana
- Department of Biochemistry
and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, United States
| | - Akbar Ali
- Department of Biochemistry
and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, United States
| | - Celia A. Schiffer
- Department of Biochemistry
and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, United States
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38
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Canini L, Chatterjee A, Guedj J, Lemenuel-Diot A, Brennan B, Smith PF, Perelson AS. A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV. Antivir Ther 2014; 20:469-77. [PMID: 25321394 DOI: 10.3851/imp2879] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct-acting antivirals. METHODS We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a Phase I study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naive and 8 were non-responders to prior pegylated IFN-α/ribavirin treatment. RESULTS In all patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg twice daily) and 0.99 at the highest dose (200 mg three times daily). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg twice daily). The second phase decline showed two different behaviours, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 day(-1)), whereas the viral decline was slower in the other patients. CONCLUSIONS Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.
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Affiliation(s)
- Laetitia Canini
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
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39
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Tong X, Li L, Haines K, Najera I. Identification of the NS5B S282T resistant variant and two novel amino acid substitutions that affect replication capacity in hepatitis C virus-infected patients treated with mericitabine and danoprevir. Antimicrob Agents Chemother 2014; 58:3105-14. [PMID: 24637689 PMCID: PMC4068480 DOI: 10.1128/aac.02672-13] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 03/10/2014] [Indexed: 12/13/2022] Open
Abstract
Baseline and posttreatment samples from hepatitis C virus (HCV) genotype (GT) 1-infected patients who received a combination of danoprevir and mericitabine from a phase II clinical study (INFORM-SVR) were analyzed. In addition to resistance monitoring, sequencing and phenotypic assays were combined with statistical analysis to identify potential novel amino acid substitutions associated with treatment outcome. The NS5B S282T substitution associated with mericitabine resistance was identified in 2/30 viral breakthrough patients and was replaced by wild-type viruses after cessation of drug treatment (during follow-up). The NS3 R155K substitution associated with danoprevir resistance was also observed in these 2 patients. All 69 GT 1a-infected patients who experienced viral breakthrough on treatment or relapsed during follow-up (relapsers) developed NS3 R155K. Among GT 1b-infected patients, substitutions at the danoprevir resistance locus NS3 D168 were observed in 15/20 subjects, whereas substitutions at the danoprevir resistance locus NS3 R155 were observed in 5/20 subjects. Interestingly, the baseline polymorphism NS5B Q47H was more prevalent in GT 1a-infected patients who achieved a sustained virologic response at follow-up week 24 (SVR24) than in non-SVR24 patients (2/13 versus 0/72), and a postbaseline NS3 S122G substitution was more prevalent in GT 1a-infected patients with viral breakthrough than in relapsers (4/22 versus 0/47). Neither substitution conferred resistance to danoprevir or mericitabine, but the substitutions reduced (NS5B Q47H) or improved (NS3 S122G) replication capacity by 2- to 4-fold. The NS5B S282T mericitabine-resistant variant was rare and did not persist once drug was discontinued. NS5B Q47H and NS3 S122G are two newly identified substitutions that affected replication capacity and were enriched in distinct treatment response groups. (This study has been registered at ClinicalTrials.gov under registration no. NCT01278134.).
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Affiliation(s)
- Xiao Tong
- Infectious Diseases Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA
| | - Lewyn Li
- Infectious Diseases Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA
| | - Kristin Haines
- Infectious Diseases Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA
| | - Isabel Najera
- Infectious Diseases Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA
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40
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Preclinical Pharmacokinetics and In Vitro Metabolism of BMS-605339: A Novel HCV NS3 Protease Inhibitor. J Pharm Sci 2014; 103:1891-902. [DOI: 10.1002/jps.23959] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Revised: 03/04/2014] [Accepted: 03/06/2014] [Indexed: 12/24/2022]
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41
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Meeprasert A, Hannongbua S, Rungrotmongkol T. Key binding and susceptibility of NS3/4A serine protease inhibitors against hepatitis C virus. J Chem Inf Model 2014; 54:1208-17. [PMID: 24689657 DOI: 10.1021/ci400605a] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Hepatitis C virus (HCV) causes an infectious disease that manifests itself as liver inflammation, cirrhosis, and can lead to the development of liver cancer. Its NS3/4A serine protease is a potent target for drug design and development since it is responsible for cleavage of the scissile peptide bonds in the polyprotein important for the HCV life cycle. Herein, the ligand-target interactions and the binding free energy of the four current NS3/4A inhibitors (boceprevir, telaprevir, danoprevir, and BI201335) were investigated by all-atom molecular dynamics simulations with three different initial atomic velocities. The per-residue free energy decomposition suggests that the key residues involved in inhibitor binding were residues 41-43, 57, 81, 136-139, 155-159, and 168 in the NS3 domain. The van der Waals interactions yielded the main driving force for inhibitor binding at the protease active site for the cleavage reaction. In addition, the highest number of hydrogen bonds was formed at the reactive P1 site of the four studied inhibitors. Although the hydrogen bond patterns of these inhibitors were different, their P3 site was most likely to be recognized by the A157 backbone. Both molecular mechanic (MM)/Poisson-Boltzmann surface area and MM/generalized Born surface area approaches predicted the relative binding affinities of the four inhibitors in a somewhat similar trend to their experimentally derived biological activities.
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Affiliation(s)
- Arthitaya Meeprasert
- Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University , 254 Phayathai Road, Pathumwan, Bangkok 10330, Thailand
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42
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Ivanisenko NV, Mishchenko EL, Akberdin IR, Demenkov PS, Likhoshvai VA, Kozlov KN, Todorov DI, Gursky VV, Samsonova MG, Samsonov AM, Clausznitzer D, Kaderali L, Kolchanov NA, Ivanisenko VA. A new stochastic model for subgenomic hepatitis C virus replication considers drug resistant mutants. PLoS One 2014; 9:e91502. [PMID: 24643004 PMCID: PMC3958367 DOI: 10.1371/journal.pone.0091502] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 02/12/2014] [Indexed: 12/17/2022] Open
Abstract
As an RNA virus, hepatitis C virus (HCV) is able to rapidly acquire drug resistance, and for this reason the design of effective anti-HCV drugs is a real challenge. The HCV subgenomic replicon-containing cells are widely used for experimental studies of the HCV genome replication mechanisms, for drug testing in vitro and in studies of HCV drug resistance. The NS3/4A protease is essential for virus replication and, therefore, it is one of the most attractive targets for developing specific antiviral agents against HCV. We have developed a stochastic model of subgenomic HCV replicon replication, in which the emergence and selection of drug resistant mutant viral RNAs in replicon cells is taken into account. Incorporation into the model of key NS3 protease mutations leading to resistance to BILN-2061 (A156T, D168V, R155Q), VX-950 (A156S, A156T, T54A) and SCH 503034 (A156T, A156S, T54A) inhibitors allows us to describe the long term dynamics of the viral RNA suppression for various inhibitor concentrations. We theoretically showed that the observable difference between the viral RNA kinetics for different inhibitor concentrations can be explained by differences in the replication rate and inhibitor sensitivity of the mutant RNAs. The pre-existing mutants of the NS3 protease contribute more significantly to appearance of new resistant mutants during treatment with inhibitors than wild-type replicon. The model can be used to interpret the results of anti-HCV drug testing on replicon systems, as well as to estimate the efficacy of potential drugs and predict optimal schemes of their usage.
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Affiliation(s)
- Nikita V. Ivanisenko
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Elena L. Mishchenko
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Ilya R. Akberdin
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Pavel S. Demenkov
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Vitaly A. Likhoshvai
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Konstantin N. Kozlov
- Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia
| | - Dmitry I. Todorov
- Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia
- Chebyshev Laboratory, St. Petersburg State University, St. Petersburg, Russia
| | - Vitaly V. Gursky
- Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia
- Theoretical Department, Ioffe Physical-Technical Institute of the Russian Academy of Sciences, St.Petersburg, Russia
| | - Maria G. Samsonova
- Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia
| | - Alexander M. Samsonov
- Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia
- Theoretical Department, Ioffe Physical-Technical Institute of the Russian Academy of Sciences, St.Petersburg, Russia
| | - Diana Clausznitzer
- Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany
| | - Lars Kaderali
- Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany
| | - Nikolay A. Kolchanov
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Vladimir A. Ivanisenko
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
- PB-soft Llc, Novosibirsk, Russia
- * E-mail:
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43
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Scola PM, Sun LQ, Wang AX, Chen J, Sin N, Venables BL, Sit SY, Chen Y, Cocuzza A, Bilder DM, D'Andrea SV, Zheng B, Hewawasam P, Tu Y, Friborg J, Falk P, Hernandez D, Levine S, Chen C, Yu F, Sheaffer AK, Zhai G, Barry D, Knipe JO, Han YH, Schartman R, Donoso M, Mosure K, Sinz MW, Zvyaga T, Good AC, Rajamani R, Kish K, Tredup J, Klei HE, Gao Q, Mueller L, Colonno RJ, Grasela DM, Adams SP, Loy J, Levesque PC, Sun H, Shi H, Sun L, Warner W, Li D, Zhu J, Meanwell NA, McPhee F. The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection. J Med Chem 2014; 57:1730-52. [PMID: 24564672 DOI: 10.1021/jm500297k] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
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Affiliation(s)
- Paul M Scola
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut, 06492, United States
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44
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Scola PM, Wang AX, Good AC, Sun LQ, Combrink KD, Campbell JA, Chen J, Tu Y, Sin N, Venables BL, Sit SY, Chen Y, Cocuzza A, Bilder DM, D’Andrea S, Zheng B, Hewawasam P, Ding M, Thuring J, Li J, Hernandez D, Yu F, Falk P, Zhai G, Sheaffer AK, Chen C, Lee MS, Barry D, Knipe JO, Li W, Han YH, Jenkins S, Gesenberg C, Gao Q, Sinz MW, Santone KS, Zvyaga T, Rajamani R, Klei HE, Colonno RJ, Grasela DM, Hughes E, Chien C, Adams S, Levesque PC, Li D, Zhu J, Meanwell NA, McPhee F. Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection. J Med Chem 2014; 57:1708-29. [DOI: 10.1021/jm401840s] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Paul M. Scola
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Alan Xiangdong Wang
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Andrew C. Good
- Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Li-Qiang Sun
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Keith D. Combrink
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Jeffrey A. Campbell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Jie Chen
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Yong Tu
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Ny Sin
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Brian L. Venables
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Sing-Yuen Sit
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Yan Chen
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Anthony Cocuzza
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Donna M. Bilder
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Stanley D’Andrea
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Barbara Zheng
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Piyasena Hewawasam
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Min Ding
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Jan Thuring
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Jianqing Li
- Department
of Discovery Chemical Synthesis, Bristol-Myers Squibb Research and Development, P.O.
Box 4000, Princeton, New Jersey 08543, United States
| | - Dennis Hernandez
- Department
of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Fei Yu
- Department
of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Paul Falk
- Department
of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Guangzhi Zhai
- Department
of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Amy K. Sheaffer
- Department
of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Chaoqun Chen
- Department
of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Min S. Lee
- Department
of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Diana Barry
- Department
of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Jay O. Knipe
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Wenying Li
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Yong-Hae Han
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Susan Jenkins
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Christoph Gesenberg
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Qi Gao
- Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
| | - Michael W. Sinz
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Kenneth S. Santone
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Tatyana Zvyaga
- Department of
Lead Discovery and Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Ramkumar Rajamani
- Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Herbert E. Klei
- Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Richard J. Colonno
- Department
of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Dennis M. Grasela
- Department of Early Clinical and Translational
Research, Discovery Medicine—Virology, Bristol-Myers Squibb Research and Development, Hopewell, New Jersey 08543, United States
| | - Eric Hughes
- Department of Early Clinical and Translational
Research, Discovery Medicine—Virology, Bristol-Myers Squibb Research and Development, Hopewell, New Jersey 08543, United States
| | - Caly Chien
- Department of Early Clinical and Translational
Research, Discovery Medicine—Virology, Bristol-Myers Squibb Research and Development, Hopewell, New Jersey 08543, United States
| | - Stephen Adams
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Paul C. Levesque
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Danshi Li
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Jialong Zhu
- Department
of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Nicholas A. Meanwell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Fiona McPhee
- Department
of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
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45
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Ehrenberg AE, Schmuck B, Anwar MI, Gustafsson SS, Stenberg G, Danielson UH. Accounting for strain variations and resistance mutations in the characterization of hepatitis C NS3 protease inhibitors. J Enzyme Inhib Med Chem 2014; 29:868-76. [PMID: 24517372 DOI: 10.3109/14756366.2013.864651] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
CONTEXT Natural strain variation and rapid resistance development makes development of broad spectrum hepatitis C virus (HCV) drugs very challenging and evaluation of inhibitor selectivity and resistance must account for differences in the catalytic properties of enzyme variants. OBJECTIVE To understand how to study selectivity and relationships between efficacy and genotype or resistant mutants for NS3 protease inhibitors. MATERIALS AND METHODS The catalytic properties of NS3 protease from genotypes 1a, 1b and 3a, and their sensitivities to four structurally and mechanistically different NS3 protease inhibitors have been analysed under different experimental conditions. RESULTS The optimisation of buffer conditions for each protease variant enabled the comparison of their catalytic properties and sensitivities to the inhibitors. All inhibitors were most effective against genotype 1a protease, with VX-950 having the broadest selectivity. DISCUSSION AND CONCLUSION A new strategy for evaluation of inhibitors relevant for the discovery of broad spectrum HCV drugs was established.
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Ivanisenko NV, Mishchenko EL, Akberdin IR, Demenkov PS, Likhoshvai VA, Kozlov KN, Todorov DI, Samsonova MG, Samsonov AM, Kolchanov NA, Ivanisenko VA. Replication of the subgenomic hepatitis C virus replicon in the presence of the NS3 protease inhibitors: a stochastic model. Biophysics (Nagoya-shi) 2014. [DOI: 10.1134/s0006350913050059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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Chaplin DA, Fox ME, Kroll SHB. Dynamic kinetic resolution of dehydrocoronamic acid. Chem Commun (Camb) 2014; 50:5858-60. [DOI: 10.1039/c4cc01125b] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
A dynamic kinetic resolution is described employing enzymatic reaction of a readily racemised azlactone with an alcohol which can provide either enantiomer of dehydrocoronamic acid.
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Affiliation(s)
- David A. Chaplin
- Chirotech Technology Centre
- Dr Reddy’s Laboratories EU Ltd
- Cambridge, UK
| | - Martin E. Fox
- Chirotech Technology Centre
- Dr Reddy’s Laboratories EU Ltd
- Cambridge, UK
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Deneke M, Dranoff J, Duarte-Rojo A. Successful eradication of genotype 4 HCV with telaprevir-based triple antiviral therapy. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2014. [DOI: 10.1016/j.rgmxen.2014.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Deneke MG, Dranoff JA, Duarte-Rojo A. [Successful eradication of genotype 4 HCV with telaprevir-based triple antiviral therapy]. REVISTA DE GASTROENTEROLOGIA DE MEXICO 2014; 79:64-66. [PMID: 24679642 DOI: 10.1016/j.rgmx.2013.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Revised: 09/03/2013] [Accepted: 09/04/2013] [Indexed: 06/03/2023]
Affiliation(s)
- M G Deneke
- División de Gastroenterología y Hepatología, Universidad de Arkansas para las Ciencias Médicas, Little Rock, AR, EE. UU
| | - J A Dranoff
- División de Gastroenterología y Hepatología, Universidad de Arkansas para las Ciencias Médicas, Little Rock, AR, EE. UU.; Servicio de Investigación, Servicio de Salud Veterans Affairs de Arkansas Central, Little Rock, AR, EE. UU
| | - A Duarte-Rojo
- División de Gastroenterología y Hepatología, Universidad de Arkansas para las Ciencias Médicas, Little Rock, AR, EE. UU..
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Efficacy and safety of danoprevir-ritonavir plus peginterferon alfa-2a-ribavirin in hepatitis C virus genotype 1 prior null responders. Antimicrob Agents Chemother 2013; 58:1136-45. [PMID: 24295986 DOI: 10.1128/aac.01515-13] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Danoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a-ribavirin in treatment-naive HCV genotype 1 (G1)-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a-ribavirin in G1-infected prior peginterferon-ribavirin null responders. Null responders (<2-log10 reduction in HCV RNA level at week 12) were given an open-label combination of 100 mg of ritonavir and 100 mg of DNV (100/100 mg DNVr) every 12 h (q12h) plus peginterferon alfa-2a-ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; ≥2-log10 decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a-ribavirin; those without an EVR discontinued all study drugs. Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) were infected with G1a. Ninety-six percent of patients had an IL28B non-CC genotype. A sustained virologic response at 24 weeks posttreatment (SVR24) was achieved in 67% of patients, with a higher rate in G1b-infected (88%) than G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No grade 3 or 4 alanine aminotransferase (ALT) elevations were observed. DNVr plus peginterferon alfa-2a-ribavirin demonstrated high SVR24 rates in HCV G1b-infected prior null responders and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01185860.).
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